Six years' experience and trends of serum 25-hydroxy vitamin D concentration and the effect of vitamin D3 consumption on these trends.

Introduction: Vitamin D (vitD) deficiency may have importance in some diseases, but there is a lack of data in our country to clarify the current situation. Our aim was to examine the basic characteristics of patients' vitD status, and the ratio of vitD deficiency and its relation to certain diseases, assess seasonality and trends, and reveal the indirect impact of the COVID-19 pandemic on vitD3 supplementation at the patient population level. Methods: Anonymized data on 25(OH)D test results were obtained from the clinical data registry of a tertiary teaching hospital covering the period between 1 January 2015 and 30 June 2021. VitD consumption (pharmacy sale) data were retrieved from the database of the National Health Insurance Fund of Hungary in order to calculate the defined daily dose (DDD)/1,000 inhabitants/day. Descriptive statistics and odds ratios with their 95% confidence intervals were calculated. The two-sample t-test and F-test were used to analyze our patients' data. Significant differences were considered if p <0.05. Results: Altogether, 45,567 samples were investigated; the mean age was 49 ± 19.1 years and 68.4% of them were female subjects. Overall, 20% of all patients had hypovitaminosis D, and just over 7% of patients had vitD deficiency. Male subjects had higher odds for hypovitaminosis or vitD deficiency (65.4 ± 28.2 nmol/L vs. 68.4 ± 28.4 nmol/L; p <0.0001). The mean 25(OH)D concentration has changed during the year, reaching a peak in September and a minimum in February. Patients with diseases of the circulatory system, genitourinary system, certain conditions originating in the perinatal period, and "sine morbo" (i.e., without a disease; such as those aged over 45 years and female teenagers) had statistically higher odds for lower 25(OH)D concentrations (p <0.00001). VitD consumption showed seasonality, being higher in autumn and winter. A slight increase started in the season of 2017/18, and two huge peaks were detected at the beginning of 2020 and 2021 in association with the COVID-19 waves. Conclusion: Our data are the first to describe data concerning vitD in our region. It reinforces the notion of vitD3 supplementation for some risk groups and also in healthy individuals. To prevent the winter decline, vitD3 supplementation should be started in September. This and the results during the COVID-19 pandemic highlight the importance of health education encouraging vitamin D3 supplementation.

Controlled randomized open label clinical study comparing the safety and efficacy of loading schedules in vitamin D deficient patients.

Rapidly restoring vitamin D levels to normal might be desirable in certain clinical situations. Larger doses of supplementation, have been shown to increase bone loss and the risk of falls. The optimal way to perform vitamin D loading safely and effectively is still not well elucidated. Our study was aimed to assess the safety and efficacy of two oral vitamin D loading protocols. Sixty-nine subjects with vitamin D deficiency (25OH-vitamin D (25(OH)D) < 20 ng/ml) were included. Thirty-five participants received 30 000 IU of vitamin D3 per week for 10 weeks (group Slower Loading Dose (SLD)) and thirty-four received 30 000 IU twice weekly for 5 weeks (group Moderate Loading Dose (MLD)) resulting in a loading dose of 300 000 IU for all subjects. Following this initial loading phase, both groups received 30 000 IU biweekly for 4 weeks to test whether the recommended daily vitamin D supplementation in range of 2000 IU dose-equivalent could maintain the achieved levels. Seventy-nine percent of those subjects treated in group SLD and everyone in group MLD achieved a 25(OH)D level of 30 ng/ml, which is the lower limit of the recommended normal range in Hungary. The mean increase in 25(OH)D was significantly higher in group MLD than in group SLD (38.6 ± 1.80 ng/ml vs 46,6 ± 1.80 ng/ml). No significant decrease was observed with the administration of the maintenance dose. There were no clinically significant changes in serum or urine calcium, and bone biomarkers in either group. Both protocols were found to be safe and effective, but the five-week dosing caused a significantly greater increase in 25(OH)D. A maintenance dose applied for four weeks after the loading protocol did not raise 25(OH)D levels further but maintained the achieved increase. The administration of 30 000 IU of vitamin D3 twice weekly for five weeks is a rapid, effective and safe way to treat vitamin D deficiency in vitamin D deficient patients.

High Frequency and Intensity Rehabilitation in 641 Subacute Ischemic Stroke Patients.

OBJECTIVES: To determine the effects of exergaming on quality of life (QoL), motor, and clinical symptoms in subacute stroke patients. DESIGN: A pseudorandomized controlled trial, using a before-after test design. SETTING: University hospital. PARTICIPANTS: Subacute, ischemic stroke outpatients (N=3857), 680 of whom were randomized and 641 completed the study. INTERVENTIONS: We determined the effects of 5 times a week twice daily (EX2; 50 sessions; n=286) and once daily (EX1; 25 sessions; n=272) exergaming and low-intensity standard care (control [CON]; 25 sessions; n=83) on clinical, mobility, blood pressure (BP), and QoL outcomes. MAIN OUTCOME MEASURES: The primary outcome was Modified Rankin Scale. Secondary outcomes were activities of daily living, 5 aspects of health-related QoL, Beck Depression Inventory, 6-minute walk test (6MWT), Berg Balance Scale (BBS), and static balance (center of pressure). RESULTS: During exercise, the peak heart rate was 134, 134, and 126 beats per minute in the EX2, EX1, and CON groups, respectively. mRS improved similarly in the EX2 (-1.8; effect size, d=-4.0) and EX1 (-1.4; d=-2.6) groups, but more than in the CON group (-0.7; d=-0.6). QoL, Barthel Index, BBS, 6MWT, and standing posturography improved more in the EX2 group and the same in the EX1 and CON groups. Systolic and diastolic resting BP decreased more in the EX2 and EX1 groups than in the CON group. The intervention effects did not differ between men (n=349) and women (n=292). CONCLUSIONS: Twice daily compared with once daily high-intensity exergaming or once daily lower intensity standard care produced superior effects on clinical and motor symptoms, BP, and QoL in male and female subacute ischemic stroke participants.

Exercise Effects on Multiple Sclerosis Quality of Life and Clinical-Motor Symptoms.

INTRODUCTION: Different therapies can improve clinical and motor symptoms of multiple sclerosis (MS) similarly, but studies comparing the effects of different exercise therapies on clinical and motor outcomes are scant. We compared the effects of exergaming (EXE), balance (BAL), cycling (CYC), proprioceptive neuromuscular facilitation (PNF), and a standard care wait-listed control group (CON) on clinical and motor symptoms and quality of life (QoL) in people with MS (PwMS). METHODS: PwMS (n = 68, 90% female; age, 47.0 yr; Expanded Disability Status Scale score 5-6) were randomized into five groups. Before and after the interventions (five times a week for 5 wk), PwMS were tested for MS-related clinical and motor symptoms (Multiple Sclerosis Impact Scale-29 (MSIS-29), primary outcome), QoL (EuroQol Five Dimensions Questionnaire), symptoms of depression, gait and balance ability (Tinetti Assessment Tool), static and dynamic balance and fall risk (Berg Balance Scale), walking capacity (6-min walk test), and standing posturography on a force platform. RESULTS: EXE, BAL, and CYC improved the MSIS-29 scores similarly. EXE and CYC improved QoL and walking capacity similarly but more than BAL. Only EXE improved gait and balance scores (Tinetti Assessment Tool). EXE and BAL improved fall risk and standing balance similarly but more than CYC. PNF and CON revealed no changes. The EuroQol Five Dimensions Questionnaire moderated the exercise effects on the MSIS-29 scores only in EXE. Changes in QoL and changes in the MSIS-29 scores correlated (R = 0.73) only in EXE. CONCLUSION: In conclusion, BAL and CYC but EXE in particular, but not PNF, can improve clinical and motor symptoms and QoL in PwMS (Expanded Disability Status Scale score 5 to 6), expanding the evidence-based exercise options to reduce mobility limitations in PwMS.

Diverse Exercises Similarly Reduce Older Adults' Mobility Limitations.

INTRODUCTION/PURPOSE: Little is known about the comparative effectiveness of exercise programs, especially when delivered at a high intensity, in mobility-limited older adults. We compared the effects of 25 sessions of high-intensity agility exergaming (EXE) and stationary cycling (CYC) at the same cardiovascular load on measured and perceived mobility limitations, balance, and health-related quality of life in mobility-limited older adults. METHODS: Randomized to EXE (n = 28) and CYC (n = 27), mobility-impaired older adults (age 70 yr) exercised five times per week for 5 wk at 80% of age-predicted maximal heart rate. Waitlisted controls did not exercise (n = 28). RESULTS: Groups did not differ at baseline in any outcomes (P > 0.05). The primary outcomes (The Short Form-36-Health Survey: EXE, 6.9%; effect size, 2.2; CYC, 5.5%, 1.94; Western Ontario and McMaster Universities Osteoarthritis Index: EXE, -27.2%, -3.83; CYC, -17.2, -2.90) improved similarly (P > 0.05). Secondary outcomes, including body mass (-3.7%), depression (-18%), and walking capacity (13.5%) also improved (P < 0.05) similarly after the two interventions. Activities of daily living, Berg Balance Score, BestTest scores, and Dynamic Gait Index improved more (P < 0.05) after EXE than CYC. Center of pressure of standing sway path improved in one of six tests only after EXE (P < 0.05). Postexercise cardiovascular response improved in EXE (P = 0.019). CON did not change in any outcomes (P > 0.05). CONCLUSIONS: When matched for cardiovascular and perceived effort, two diverse high-intensity exercise programs improved health-related quality of life, perceived mobility limitation, and walking capacity similarly and balance outcomes more in mobility-limited older adults, expanding these older adults' evidence-based exercise options to reduce mobility limitations.

Randomized clinical trial to comparing efficacy of daily, weekly and monthly administration of vitamin D3.

The comparative efficacy and safety profiles of selected daily 1000 IU, weekly 7000 IU and monthly 30,000 IU vitamin D 3-not previously investigated-will be evaluated. Here, a prospective, randomized clinical trial, comparing efficacy and safety of a daily single dose of 1000 IU (group A) to a once-weekly 7000 IU dose (group B), or monthly 30,000 IU dose (group C) of vitamin D3. The present study is a controlled, randomized, open-label, multicenter clinical trial, 3 months in duration. Sixty-four adult subjects with vitamin D deficiency (25OHD<20 ng/ml), were included according to the inclusion and exclusion criteria. Dose-responses for increases in serum vitamin 25OHD were statistically equivalent for each of the three groups: A, B and C. Outcomes were 13.0 ± 1.5; 12.6 ± 1.1 and 12.9 ± 0.9 ng/ml increases in serum 25OHD per 1000 IU, daily, weekly and monthly, respectively. The treatment of subjects with selected doses restored 25OHD values to levels above 20 ng/ml in all groups. Treatment with distinct administration frequency of vitamin D3 did not exhibit any differences in safety parameters. The daily, weekly and monthly administrations of daily equivalent of 1000 IU of vitamin D3 provide equal efficacy and safety profiles.

Role of salsolinol in the regulation of pituitary prolactin and peripheral dopamine release.

(R)-Salsolinol (SAL), a dopamine (DA)-related tetrahydroisoquinoline, has been found in extracts of the neuro-intermediate lobes (NIL) of pituitary glands and in the median eminence of the hypothalamus obtained from intact male rats and from ovariectomized and lactating female rats. Moreover, analysis of SAL concentrations in NIL revealed parallel increases with plasma prolactin (PRL) in lactating rats exposed to a brief (10 min) suckling stimulus after 4-h separation. SAL is sufficiently potent in vivo to account for the massive discharge of PRL that occurs after physiological stimuli (i.e. suckling). At the same time, it was without effect on the secretion of other pituitary hormones. It has been also shown that another isoquinoline derivative, 1-methyldihydroisoquinoline (1MeDIQ), which is a structural analogue of SAL, can dose-dependently inhibit the in-vivo PRL-releasing effect of SAL. Moreover, 1MeDIQ can inhibit the elevation of plasma PRL induced by physiological stimuli, for example suckling, or in different stressful situations also. 1MeDIQ also has a psycho-stimulant action, which is fairly similar to the effect of amphetamine, i.e. it induces an increase in plasma catecholamine concentrations. It is clear from these data that this newly discovered endogenous compound could be involved in regulation of pituitary PRL secretion. It has also been observed that SAL is present in peripheral, sympathetically innervated organs, for example the atrium, spleen, liver, ovaries, vas deferens, and salivary gland. Furthermore, SAL treatment of rats results in dose-dependent and time-dependent depletion of the DA content of the organs listed above without having any effect on the concentration of norepinephrine. More importantly, this effect of SAL can be completely prevented by amphetamine and by 1MeDIQ pretreatment. It is clear there is a mutual interaction between SAL, 1MeDIQ, and amphetamine or alcohol, not only on PRL release; their interaction with catecholamine "synthesis/metabolism" of sympathetic nerve terminals is also obvious.

Binding site of salsolinol: its properties in different regions of the brain and the pituitary gland of the rat.

It has been recently shown that salsolinol (SAL) is present in the hypothalamic neuroendocrine dopaminergic (NEDA) system and appears to be a selective and potent stimulator of prolactin (PRL) secretion in the rat. Furthermore, the lack of interference of SAL with 3H-spiperone binding in the striatum and the anterior lobe (AL) of the pituitary gland has been also demonstrated. These data clearly indicate that SAL does not act at the dopamine (DA) D(2) receptors, and suggest that SAL supposedly has a binding site through which the secretion of PRL may be affected. Therefore, binding of 3H-SAL to different regions of the central nervous system (CNS) has been investigated. Specific and saturable binding has been detected in the striatum, cortex, median eminence and in the hypothalamus as well as in the AL and the neuro-intermediate lobe (NIL) of the pituitary gland. K(D) values of the bindings were in the nanomolar range in all tissue tested. 3H-SAL displacing activity of several agonists and antagonists of known DA receptors have also been tested. It has been found that DA and in a lesser extent, apomorphine could displace 3H-SAL, but other DA receptor specific ligands have not been able to affect it. Furthermore, several pharmacologically active compounds, selected on the basis of their influence on DA synthesis, transport mechanisms and signal transduction, have also been tested. Neither mazindol (a selective DA transporter inhibitor) nor clonidine (an alpha(2)-adrenoreceptor agonist) could alter SAL binding. At the same time, L-dopa, carbidopa, benserazide and alpha-methyldopa were able to displace 3H-SAL. The possible changes in SAL binding due to physiological and pharmacological stimuli, like suckling stimulus and reserpine pretreatment (that blocks vesicular monoamine transport in DA terminals), respectively, have also been investigated. In the NIL of the pituitary gland and in the median eminence of the hypothalamus the binding decreased following 10 min of suckling stimulus compared to the binding detected in the same tissues obtained from mothers separated from their pups for 4h and not allowed to be suckled. At the same time, there were no changes in the binding at the AL and striatum. Following reserpine pretreatment that has completely prevented PRL releasing effect of SAL, the binding was significantly augmented. These results support our assumption that SAL should have specific binding sites through which it can affect PRL secretion. Furthermore, it clearly suggests that it may regulate DAergic neurotransmission of NEDA neurons by an altered intracellular or intraterminal synthesis and/or distribution of hypophysiotropic DA.

Physiological and pathological angiogenesis in the endocrine system.

Formation of new blood vessels occurs in many physiological states (during development of the embryo, cycling changes of the female reproductive tract), as well as in pathological processes (such as diabetic retinopathy and wound healing). Angiogenesis has been shown to be related to tumor formation, prognosis, and response to treatment in many tumor types. Intratumoral microvessels can be related to tumor behavior or hormone secretion in different endocrine tumors. For example, invasive prolactinomas are more vascular than noninvasive adenomas; a surgical approach is more successful in macroprolactinomas with lower microvessel density. A higher number of microvessels have been found in papillary thyroid carcinomas during recurrences. A correlation between microvessel count and prognosis in papillary and medullary thyroid carcinomas has been suggested. Several stimulating and inhibiting factors involved in the regulation of angiogenesis have been identified. Among them, vascular endothelial growth factor (VEGF) has been shown to be critically involved in angiogenesis and also in the neovascularization of solid tumors. Dopamine agonists (already in clinical use for prolactinomas) have potent inhibitory actions on VEGF signaling, and thus may be a new tool in antiangiogenic therapy. Secretion of VEGF in the great majority of human pituitary adenomas is inhibited by dexamethasone. This suggests that glucocorticoids can be considered in the treatment of certain pituitary tumors. The cyclic nature of angiogenesis in the female reproductive tract indicates that stimulation or inhibition of paracrine angiogenic factors may lead to new approaches for being able to influence reproductive endocrine disorders. Experimental and clinical aspects of interactions between angiogenic factors and tumor growth of the endocrine system are also discussed.

Dexamethasone and adrenocorticotropin suppress prolactin secretion in humans.

It has been demonstrated that the regulatory pathways mediating basal and/or stimulus-induced prolactin (PRL) release in mammals are highly sensitive to adrenal corticoid inhibitory influence. We have investigated the effect of four different doses of dexamethasone (DEX) and the effect of adrenocorticotropin on PRL secretion in 197 patients (169 female, 28 male; age: 18-66 yr) with suspected hypercortisolemia--but only those with a normal glucocorticoid suppression test were involved in the study--and in 66 female patients (age: 18-39 yr) with suspected adrenocorticotropin-dependent hyperandrogenism. Overnight (1 mg), low-dose (0.5 mg every 6 h for 2 d), high-dose (2 mg every 6 h for 2 d), and long-lasting administration of DEX (0.5 mg every 6 h for 5 d) resulted in a significant decrease in PRL levels compared to the baseline. Similarly, a reduction in PRL levels could be detected following injection of adrenocorticotropin (250 microg). In hyperprolactinemic patients, the DEX-induced increase in PRL (APRL, expressed in percentage of baseline) was significantly larger compared with normoprolactinemic subjects in all groups except those who received high-dose DEX) or adrenocorticotropin. These data clearly indicate that the secretory function of PRL cells in humans is sensitive to changes in the activity of the hypothalamo-pituitary-adrenal axis in a dose-dependent manner.

Physiological role of salsolinol: its hypophysiotrophic function in the regulation of pituitary prolactin secretion.

We have recently observed that 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) produced by hypothalamic neurons can selectively release prolactin from the anterior lobe (AL) of the pituitary gland. Moreover, high affinity binding sites for SAL have been detected in areas, like median eminence (ME) and the neuro-intermediate lobe (NIL) that are known terminal fields of the tuberoinfundibular DAergic (TIDA) and tuberohypophysial (THDA)/periventricular (PHDA) DAergic systems of the hypothalamus, respectively. However, the in situ biosynthesis and the mechanism of action of SAL are still enigmatic, these observations clearly suggest that sites other than the AL might be targets of SAL action. Based on our recent observations it may be relevant to postulate that an "autosynaptocrine" regulatory mechanism functioning at the level of the DAergic terminals localized in both the ME and NIL, may play a role in the hypophyseotrophic regulation of PRL secretion. Furthermore, SAL may be a key player in these processes. The complete and precise mapping of these intra-terminal mechanisms should help us to understand the tonic DAerg regulation of PRL secretion. Moreover, it may also give insight into the role of pre-synaptic processes that most likely have distinct and significant functional as well as pathological roles in other brain areas using DAergic neurotransmission, like striatonigral and mesolimbic systems.

Prolactin influences proliferation and apoptosis of a human IgE secreting myeloma cell line, U266.

In certain types of solid tumours and lymphomas prolactin (PRL) potentiates tumour cell proliferation and exerts anti-apoptotic effect. Tumour cells themselves can produce PRL and express PRL-receptors. Hyperprolactinemia is associated with different tumours, also. Multiple myeloma (MM) is a haematological malignancy caused by the clonal expansion of terminally differentiated plasma cells in the bone marrow. Recently, we demonstrated PRL immunostaining in bone marrow cells of MM patients and an elevated level of serum PRL of MM patients with advanced disease. In the present study, we tested the effect of PRL on a U266 human myeloma cell line and demonstrated constitutive and melphalan-stimulated intracytoplasmic PRL in U266 cells. Exogeneous PRL inhibited the proliferation and immunoglobulin (Ig) production of U266 myeloma cells. Concerning etoposide-induced apoptosis, PRL had a double-faceted effect depending on the applied dose: high, pharmacological doses (corresponding to hyperprolactinemia), inhibited apoptosis, whereas near physiological doses exerted a pro-apoptotic effect. These data indicate a definite effect of PRL on a human myeloma cell line. We demonstrated a direct inhibition of PRL on tumour cell growth, while its reciprocal effect on apoptosis refers to an important regulatory role of PRL.